H2 Receptor Antagonists for PUD Lecture 1

Question 1

Biosynthesis of Histamine

Answer 1

Decarboxylation of histidine (amino acid)

Location:
- Mast cells
- Basophils and eosinophils
- Enterochromaffin-like cells (stomach)
- Histaminergic neurons in CNS

Question 2

H1 Receptors

Answer 2

Location and Function

CNS
- promotes wakefulness, decreased appetite (anorexic), motion sickness, emesis

Periphery (vascular, bronchial smooth muscle, endothelium, primary sensory afferents (skin)) - bronchoconstriction, vasodilation, increased vascular permeability, edema, increased nociception, itch, urticaria

Question 3

H2 Receptors

Answer 3

Parietal cells (stomach)
- stimulation of gastric acid secretion

Vascular smooth muscle
- Vasodilation (minor)

Question 4

General Classes of Drug Affecting the Actions of Histamine

Answer 4

Mast Cell Stabilization
- Beta-adrenergic agonists
- Chromones (e.g. cromolyn sodium)

H1 receptor antagonist for hypersensitivity/allergic reactions and various other “off-target” uses

H2 receptor antagonists for inhibition of gastric acid secretion

Question 5

H2 Histamine Receptor Properties

Answer 5

G-protein coupled receptor

Stimulates adenylyl cyclase (AC), activating cAMP/PKA signaling

Major presence in gastric parietal cells where it stimulates acid secretion

Minor presence in bronchial and vascular smooth muscle where it causes relaxation (broncho- and vaso- dilation)

Question 6

Therapeutic Uses of H2 Receptor Antagonists

Answer 6

Peptic ulcer disease

Gastroesophageal reflux disease (GERD)

Dyspepsia

Prophylaxis of stress ulcer

Question 7

Muscarinic Receptor Antagonists

Answer 7

Targets the M3

Question 8

H2 Blockers

Answer 8

Targets the H2 receptor

Question 9

PPIs

Answer 9

Target the H+ / K+ ATPase (Proton Pump)

Question 10

Antibiotics

Answer 10

Targets H. Pylori

Question 11

Prostaglandins (PGE2 & PGI2)

Answer 11

Target EP3

Question 12

Determinants of Peptic Ulcer Disease (PUD)

Answer 12

H. Pylori infection
- 70% of patients with gastric ulcers
- > 95% of patients with duodenal ulcers

NSAID use associated with ~30% of gastric ulcers

Excess acid production

Question 13

General Classes of Drugs Used for Treatment of PUD

Answer 13

Proton Pump (H+ / K+ -ATPase) Inhibitors (PPIs)

H2 Histamine Receptor Antagonists (H2RAs)

Antibiotics for the elimination of H. Pylori

Muscarinic Receptor Antagonists

Prostaglandins

Mucosal Protective Agents

Antacids

Question 14

H2 Histamine Receptor Antagonists (H2RAs)

Answer 14

Highly selective to H2 receptor

Reversible, competitive inhibition

Suppress acid secretion by ~70%

Rapidly absorbed after oral administration

Mostly renal elimination

Terminal half-life = 1 to 3 hours

Relatively few adverse effects, except for cimetidine

Cimetidine = inhibits a number of CYPs and has the potential for DDI (drug-drug interactions) and has some anti-androgenic activity that can cause gynecomastia

Question 15

H2RA Drugs

Answer 15

Cimetidine
Famotidine
Nizatidine

Question 16

Proton Pump (H+ / K+ - ATPase) Inhibitors (PPIs)

Answer 16

Highly selective for the gastric H+ / K+ - ATPase

Irreversible, noncompetitive inhibition via covalent binding

All prodrugs requiring activation in an acidic environment; must reach the parietal cell by the way of blood

Enteric-coated to prevent degradation in the stomach and to promote absorption in the small intestine

Short half life = 60-90 mins

Long half life = 24-48 hours

Extensively metabolized by CYP3A4 and CYP2C19; potential drug-drug interactions

Suppress acid secretion by 80-95%

Relatively few adverse effects, most common being nausea, abdominal pain, constipation, flatulence and diarrhea

Some concern that chronic use may increase risk of bone fractures and increased susceptibility to infections, esp. C. difficile

Hypergastrinemia may cause rebound hypersecretion of acid upon discontinuation of therapy

Uses are similar to H2 receptor antagonists, but also include prophylaxis of NSAID-induced GI toxicity and Zollinger-Ellison syndrome (gastrin-secreting tumor)

Question 17

PPI Drugs

Answer 17

Omeprazole (Prilosec)
Lansoprazole (Prevacid)
Pantoprazole (Protonix)
Rabeprazole (AcipHex)